Brain and retinal microglia in health and disease: An unrecognized target of the renin–angiotensin system

Abstract

Summary Microglia are the resident immune cells within the brain and retina, commonly known as the macrophages of the central nervous system (CNS). Microglia survey the surrounding milieu to eliminate invading microbes, clear cellular debris and enforce programmed cell death by removing apoptotic cells. Complementary to their ‘house‐keeping’ role, microglia are capable of releasing brain‐derived neurotrophic factor (BDNF), as well as various anti‐inflammatory cytokines that sustain and support neuronal survival. Although microglia are essential for maintaining a healthy CNS, paradoxically they may undergo phenotypic changes to influence numerous neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease. Understanding the underlying mechanisms that determine whether microglia are supportive or toxic could elucidate novel and more effective therapeutic targets to treat an array of neurological and retinal diseases. Although relatively little is known about the influences that evoke phenotypic changes in the microglial population, there is accumulating evidence illustrating an interaction with the renin‐angiotensin system (RAS). The angiotensin AT1 and AT2 receptors may have differential roles in mediating the activity of microglia. Understanding the actions of these angiotensin receptors will be important in defining whether microglia are an important therapeutic target for RAS blockade in brain and ocular diseases.

Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury

“…We have previously shown that IL-10 co-localizes with neurons after ischemic stroke (Fouda et al, 2013). Moreover, C21 is speculated to stimulate an IL-10 producing, anti-inflammatory microglia phenotype (McCarthy et al, 2013). C21 may also increase IL-10 production from systemic immune cells.…”

Retinal Microglia in Glaucoma

“…Functions of the glial cells are, among others, to supply and support the structure and architecture of the whole system, to enable and facilitate the nourishment of the neurons, to help building up the system, to keep the system functioning by removing cell debris, and to play an immunologic role. 2,9 In general, the neuroglial cells are smaller than the neural cells, but outnumber them by a factor of 5 to 10. 10 The ratio of glial cell number to neural cell number is highest in the basal ganglia, diencephalon, and brainstem (ratio > 10), followed by the cerebral cortex (ratio: 3 to 4), and it is relatively low in the cerebellum (ratio: 0.1 to 0.3).…”

“…Among other properties, they have the potential to release various factors that directly and/or indirectly promote regeneration in the injured nervous system. [1][2][3][4] It was the purpose of this review to elucidate the importance of the retinal microglial cells in the course, but not as the cause, of glaucomatous optic neuropathy, and to illustrate the role retinal microglial cells take in the interval between the primary damage set to the retinal ganglion cell axons, and the final death and disappearance of the ganglion cell axons and cell bodies. As the reaction of the microglial cells to a damaged retinal ganglion cell may not markedly depend on the primary causative mechanism, the features of the retinal microglial cells as described below with respect to glaucomatous optic neuropathy may also hold true for nonglaucomatous optic nerve damage such as in diabetic retinopathy or anterior ischemic optic neuropathy.…”

The Vasoneuronal Effects of AT1Receptor Blockade in a Rat Model of Retinopathy of Prematurity

“…36 Microglia have also been implicated in vascular development and in the maintenance of neuronal integrity in the central nervous system. 36,37 Moreover, release of proinflammatory cytokines from microglia is thought to contribute to the development of vascular pathology in OIR. 38 We examined whether microglia were altered in OIR or by valsartan treatment (Fig.…”

“…These findings are consistent with the emerging role of the RAS in the activation status of microglia in both the brain and retina. 37 …”